This proposal will study the specific subpopulations of cells in the liver that are involved during the regeneration of damaged and diseased liver. A mouse model of the human hereditary disease tyrosinemia type I (HTI) will be used, this disease is characteristic of several inherited metabolic diseases in which one gene is absent. HTI is due to the loss of the enzyme fumarylacetoacetate hydrolase (FAH) resulting in progressive liver damage and a high frequency of hepatocellular cancer. It has been discovered that hepatocytes that express this enzyme possess a selective growth advantage over cells that do not express FAH in the liver. Isolation and transplantation of specific subpopulations of FAH expressing cells into the livers of FAH deficient mice should allow for the identification of specific liver cell subpopulations which are involved in liver regeneration. This proposal also studies the use of retroviral gene therapy by transducing cells in FAH deficient mice with a FAH expressing retrovirus and studying their selective growth advantage. These experiments, determining the regenerative subpopulation of liver cells and treatment of FAH deficient mice with retroviral gene therapy, could prove valuable in designing a treatment for human tyrosinemia and other liver and related metabolic diseases.